Certain 3-acylthioalkylenethio-5-alkylthio - 4-cyano-isothiazoles and 5-acylthioalkylenethio - 3 - alkylthio - 4-cyano-isothiazoles



United States Patent 3,481,946 CERTAIN 3-ACYLTHIOALKYLENETHIO-5-ALKYL- THIO 4-CYANO-ISOTHIAZOLES AND S-ACYL- THIOALKYLENETHIO 3 ALKYLTHIO 4- CYANO-ISOTHIAZOLES Karl Giinther Schmidt, Giinther Mohr, and Sigmund Lust, Darmstadt, Germany, assignors to E. Merck A.G., Darmstadt, Germany No Drawing. Filed Apr. 18, 1967, Ser. No. 631,577 Claims priority, application Germany, Apr. 23, 1966, M 69,263 Int. Cl. C07d 91/12 US. Cl. 260-302 7 Claims ABSTRACT OF THE DISCLOSURE As new compounds suitable as fungicidal agents, there are provided isothiazole derivatives of the formulae:

a s-bu ON lain-$43041: wherein and This invention relates to derivatives of 4-cyano-isothia zoles, and in particular to those derivatives having fungicidal properties.

An object of this invention, is, therefore, to provide novel chemical compounds and, concomitantly, intermediates, by-products, and processes relating to the production of such compounds.

comprises isomeric compounds of Formulae Ia and/or R represents alkylene of l-4 carbon atoms;

R represents alkyl of 1-4 carbon atoms; phenyl;

or phenyl substituted by l-3 hydroxy or alkyl groups, halogen atoms, or methylenedioxy; and

R represents alkyl of 1-4 carbon atoms.

These fungicidal agents can be incorporated with conventional carriers and/or fillers, and, if desired, additional conventional fungicides.

The activity of the novel compounds was determined in the spore germination test and in the infection test. The LD and LD were determined, i.e., that amount of active agent (measured in mg./ 100 cm?) which prevents, to an extent of 50% and 95%, respectively, the germination of the fungus spores in the spore germination test, and the growth of the fungus on the leaf surface in the infection test.

The novel compounds were compared with the known highly effective fungicide N-trichloromethylthio-tetrahydrophthalimide, as a standard. In the spore germination test on Venturia the novel fungicides 3-acetylthio-methylthio-S-methylthio-4-cyano-isothiazole and S-acetylthiomethylthio-3-methylthio-4-cyano-isothiazole are two to three times more effective than the standard compound, whereas approximately the same activity is observed when using these agents in the spore germination test on Alternaria. Similar data was obtained in the infectionpreventing experiment in the leaf spraying test on Plasmopara viticola wherein approximately the same LD is obtained as in using N-trichloromethylthio-tetrahydrophthalimide. The following table presents a summary of the data:

TAB LE Spore germination test on Venturia Alternaria inaequalis spec.

N -trichloromethylthio-tetrahydrophthalimide (standard) 1 1 S-acetylth omethylthio-B-methylthio-4-eyano-isothiazo1e 2 1 5-acetylthlomethylthio-li-methylthio-4-eyano-isothiazole 3 1. 4

Another object is to provide novel compositions and methods for effecting fungicidal activity.

Upon further study of the specification and claims, other objects and advantages of the present invention will become apparent.

To attain these objects, it was discovered that a group of 4-cyano-isothiazoles possess excellent fungicidal properties, being particularly effective on the known fungi Venturia inaequalis, the cause of apple scab, on Alternaria spec., the leaf spot causing fungus, and on Plasmapara viticola, the cause of false grapevine mildew. The

In view of the actual tests, it is reasonable to expect that the fungicidal agents will also exhibit a finite fungicidal activity with fungi of the following genus: Alternaria, Botrytis, Bremia, Cercospora, Cladosporium, Colletotrichum, Helminthosporium, Monilia, Peronospora, Piricularia, Phytophthora, Septoria, Sklerotinia, Venturia.

Referring to the novel compounds of Formulae Ia and lb, R represents methylene, ethylene, as Well as the straight-chain or branched propylene and butylene residues.

R is either an alkyl residue of l-4 carbon atoms, i.e.,

group of fungicidal 4-cyano-isothiazoles of this invention methyl, ethyl, nor isopropyl, or n-, sec.-, or tert.- butyl;

or R can also be a phenyl residue Which is substituted, if desired. Suitable substituted phenyl radicals include among others, for example, hydroxyphenyl such as m-, p-hydroxyphenyl, 2,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,4,6-trihydroxyphenyl, alkyl phenyl wherein alkyl is of l-4 carbon atoms, such as o-, m-, or p-tolyl, xylyl, and 2,4,6-trimethylphenyl; halogen-substituted phenyl residues, such as 2,4-dihalogenophenyl, 3,5-dihalogenophenyl, or 2,4,6-trihalogenophenyl residues, the halogen atoms being preferably chlorine, bromine, or iodine; and phenyl substituted by methylenedioxy, preferably 2,3-methylenedioxyphenyl. Furthermore, it is possible for R to represent mixed phenyls such as 2-alkyl, 4-halo, 6-hydroxyphenyl and the like.

R represents the same alkyl residues named as substituents in R above.

Preferred embodiments embraced by Formulae Ia and Ib are those in which:

(a) R represents CH or CH CH R represents alkyl of 1-4 carbon atoms or phenyl; and R represents alkyl of 1-4 carbon atoms;

(b) R represents CH R represents CH C H or C H and R represents CH or C H Single species preferred include the following 4-cyanoisothiazoles:

The novel compounds can be produced, for example, by reacting 4-cyano-isothiazoles of Formulae Ila and/ R represents an alkali, ammonium, or amine salt cation,

or one equivalent of an alkaline earth cation; and

R is R or R with an u-halogenoalkylacyl sulfide of Formula III R COSR Hal (III) wherein R and R have the above-indicated meanings; and Hal represents halogen, preferably C1 or Br.

The above salts of 3,S-dimercapto-4-cyano-isothiazoles employed as the starting material (11a and 11b) are produced in accordance with conventional methods, for example, by reacting malonic acid dinitrile with carbon disulfide in the presence of the corresponding salt-forming base; the solvent preferably used in this reaction is alcohol or acetonitrile. The 1,1-dicyano-2,Z-dimercaptoethene,

which is formed first, reacts with sulfur under ring closure so that the corresponding 4-cyano-isothiazole is produced. If compounds of Formula He or Ilb are used as the starting material wherein R =R an alkylation step is subsequently performed, in accordance with conventional methods.

The starting material of type IIa (or 11b) in which R =R =Na is known (cf. I. Organic Chemistry, 29, 665 (1964)); those of formula IIa (or IIb) with R =R can be prepared analogously. The compounds of Formula III are either known or can be prepared by conventional methods (cf., f.e. Liebigs Annalen, 623, 92 (1959)).

When a compound of Formula IIa or IIb having R ='R employed as the starting material, a subsequent treatment with an alkylating agent is conducted to intro duce the substituent R or alternatively, the alkylation step can be conducted first. Depending upon the reaction route and reaction conditions, two isomeric compounds are obtained, wherein the acylthio-methyl-thio group (-R COSR is either in the 3- or 5-position, and the alkyl group R is correspondingly located either in the 5- or in the 3-position.

Preferred salts of the 4-cyano-isothiazoles of Formulae Hz: or 1111 are particularly the alkali salts, such as sodium and potassium; the alkaline earth salts such as magnesium and calcium; ammonium and amine salts. With respect to amine salts, tertiary amine is preferred, but secondary and primary amines can also be employed. Since the cation does not directly participate in the reaction and does not appear in the final product, a wide variety of amine salts can be employed. However, in general, the substituted ammonium cations contain no more than 16 carbon atoms, specific examples of such amines being, for example: mono-, di-, and trimethylamine; mono-, di-, and triethylamine; mono-, di-, and tripropylamine; mono-, di-, and tributylamine, particularly N-tert.-butylamine and isobutylamine, nor tert.-octylamine, n-decylamine and isodecylamine, n-dodecylamine, and tert.-dodecylamine. Straight or branched chain amines can be employed, it being preferred, of course, to use those readily available amines of commerce.

Novel intermediates are those of Formula IV as fol- R represents R -CO-SR or R and R to R have the above-indicated meanings.

Specific novel intermediates include the sodium and potassium salts of the following 4-cyano-5-mercapto-isothiazoles:

3-methylthio- 3-ethylthio- 3-acetylthio-methylthio- 3-propionylthio-methhylthio- 3-butyryltl1io-methylthio- 3-benzoylthio-methylthio- 3- (Z-acetylthio-ethylthio) For reacting the compounds of Formula IIa or IIb with the u-halogenoalkylacyl sulfides of Formula III, as well as for the alkylation step which follows in certain cases, all solvents can be employed which are conventionally used for such reactions, for example, water or organic solvents, such as methanol, ethanol, propanol, isopropanol, butanol, acetone, dioxane, tetrahydrofuran, dimethylformamide, and benzene, or also mixtures of these solvents.

Which of the two different isomers is formed is influenced by the selection of the starting material and the solvent. Thus, one of the two isomeric 3(5)-acylthioalkylthio 5(3) alkylthio 4 cyano isothiazoles is produced when anhydrous solvents are employed in all instances. In this case, it is advantageous first to react the starting material with a 2-ha1ogenoalkylacyl sulfide and thereafter with an alkylating agent.

Conversely, the isomer of the product produced on an anhydrous basis, is selectively obtained when the starting compound is one of Formula Ila or IIb wherein and if this substituent R, has previously been obtained by alkylation of the basic 4-cyano-isothiazole in the presence of water. The resultant salt of the alkylthio-mercapto-4 cyano-isothiazole -(IIa or IIb) is preferably first isolated from the aqueous solution and then reacted with an ahalogenoalkylacyl sulfide, this later step being preferably conducted in an anhydrous organic solvent. It is apparent, therefore, that the solvent present during the introduction of the alkyl group R is an important factor in determining which one of the isomeric compounds is obtained.

The reaction temperatures for these reactions generally range betwen 5 C. and the boiling point of the solvent employed. Normally, about /2 to 5 hours are required for conducting the reaction. The isolation and the working up of the novel compounds are conducted in a conventional manner.

For conducting a separate alkylation step, all processes can be employed which are conventional for the alkylation of mercaptides. Particularly suitable reactions are those with alkyl sulfates, alkyl halogenides, and arylsulfonic acid alkyl esters, and especially high yields are obtained when using dimethyl sulfate, methyl bromide, and methyl iodide. The reaction conditions are the same as those described in the literature for these reactions, with respect to the solvent employed, the reaction temperatures, and the reaction times. Pertinent literature is found, for example, in Houben-Weyl, Methoden der organischen Chemie, Volume IX, pages 103-113 (1955).

The isothiazoles of this invention can be beneficially combined with other fungicides, such as, among others:

Copper-containing fungicides, e.g., cuprous oxide, cop per oxychloride, copper sulfate, basic copper carbonate, copper zinc chromate, boreaux mixture (mixture of copper sulfate and hydrated lime), copper naphthenate, copper 8 hydroxyquinolinate; sulfur-containing fungicides, e.g., wetting sulfur, polysulfides, lime-sulfur mixtures (aqeuous solutions of calcium polysulfides and calcium thiosulfate); mercury-containing fungicides, e.g., mercuric chloride, phenylmercuric acetate, benzoate and chloride, ethylmercuric acetate and chloride, Z-methoxyethylmercuric chloride, silicate and phosphate, (3-chloromethoxypropyl)-mercuric acetate, ethylmercuric-2,3-dihydroxypropyl mercaptide, N-(ethylmercuri) -p-toluolsulfonic acid auilide, N-(methylmercuri) N- (ethylmercun')- and N-(phenylmcrcuri)-1,4,5,6,7,7-hexachlorobicyclo[2,2,1]hept 5-ene-2,3-di-carboximide, S-(ethylmercuri)-thiosalicylic acid sodium salt, methylmercuri-S-hydroxyquinolinate, methylmercuridicyandiamide, phenylmercuriurea, phenylmercuritriethanolammonium lactate, phenylmercurimonoethanolammonium acetate; tin-containing fungicides, e.g., triphenyltin hydroxide and acetate; thiocarbamates, e.g., the Na, K-, NH Zn-, Feand Mn-salts of monomethyldithio-, dimethyldithioand ethylene-bis-dithio carbamic acids; thiurams, e.g., tetramethylthiuram disulfide, polyethylenethiuram disulfide; Z-mercaptobenzothiazol and its salts; pentachlorophenol; chloronitrobenzenes, e.g., pentachloronitrobenzene, 2,3,5, 6-tetrachloronitrobenzene, trichlorodinitroand trichlorotrinitrobenzenes; 1-thiocyanato-2,4-dinitrobenzene; hexachlorobenzene; 2-sec.butyl4,6-dinitrophenyl-3-methyl-2'- butenoate; 7 methyl-1,3-dithiolo[4,5-b]-chinoxalin-2-on; N,N dimethyl-N'-phenyl-N'-(dichlorofiuoromethylthio)- sulfamide; quinone derivatives, e.g., tetrachloro-p-benzoquinone, 2,3-dichloro-1,4-naphthoquinone, 2,3-dicyano- 1,4 dithiaanthraquinone; N-trichloromethylthio-1,2,3,6- tetrahydrophthalimide, N trichloromethylthio-phthalimide, N (1,1,2,2-tetrachloroethylthio)-1,2,3,6-tetrahydrophthalimide; 2,4 dinitro-6-(a-methylheptyl)-phenyl crotonate; N-dodecylguanidine acetate; 3,5-di1rnethyl-1,3,5- 2H tetrahydro thiadiazine-Z-thione; 2,4-dichloro-6-(2- chloroanilino) 1,3,5-triazine; S-Amino-l-(bis-dirnethylamino-phosphinyl)-3-phenyl-1,2,4-triazole; as well as antibiotics, e.g., tetracycline, chlorotetracycline, hydroxytetracycline, streptomycins, cycloheximide, cellocydine (acetylenedicarboxamide); or 2,6-dichloro-3,5-dicyano-4-phenylpyridine.

The isothiazoles of this invention can be incorporated in all forms of compositions suitable for fungicidal applications, and contain generally about 1 to of the active agent. Adding conventional carriers and/or fillers, there can be produced, for example, sprayable or atomizable agents. Additives such as dressing agents for the preservation of seed; dispersing agents and/or wetting agents can be added. When using the appropriate additives, it is also possible to produce solutions or emulsions of the novel substances, which can, for example, be atomized as aerosols.

More specifically, the agents can be incorporated with pulverulent solids to form sprayable powders or dusting compositions. They also can be incorporated with surface active agents and thickening agents to form sprayable dispersions. Additives and fillers used in this connection are the conventional ones, such as, for example, bole, kaolin, bentonite, ground shale, talc, chalk, dolomite, or kieselguhr, if solid preparations are concerned. For liquid formulations, xylene, solvent naphtha, petroleum, acetone, cyclohexane, dimethyl formamide, or aliphatic alcohols are preferably used as solvents. The emulsion concentrates thus prepared can be marketed as such. Prior to use, the emulsion concentrates are diluted with water in the usual manner. Due to the low solubility of the active agents in organic solvents, it is, however, preferable to formulate them as aqueous dispersions. As organic thickening agents for such dispersions, the following can, e.g., be used: methyl, ethyl, carboxymethyl and hydroxyethyl cellulose, tragacanth, dextrines, alginic acids and their salts, polyvinyl alcohol. Typical inorganic thickening agents are bentonite, attaclay and hectorite. As surface active agents there can be used all wetting and dispersing agents, which are usually applied in pesticides, preferably in an amount of about 0.01 to 1% calculated on the basis of the preparation form for use. Suitable wetting and/or dispersing agents are alkyl benzene sulfonates, alkyl naphthalene sulfonates, polyoxyethylene esters of fatty and resinic acids, alkyl phenol polyglycol ethers.

The compounds being employed as fungicides in a pest control program are generally applied to the locus subject to infestation in a quantity per hectare of about 1 to 50 kg.; preferably about 2.5 to 25 kg. More or less active ingredient can be used in dependence on the vegetation involved.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative.

(A) PREPARATION OF THE ACTIVE AGENTS Example 1 At room temperature, 12.4 g. chloromethyl acetyl sulfide, dissolved in 10 ml. ethanol, are added to 21.8 g. of the disodium salt of 3,5-dimercapto-4-cyano-isothiazole, suspended in 300 ml. absolute ethanol. After the entire amount has been added dropwise, the reaction mixture is agitated for 12 hours at 60 C. Thereafter, 14.2 g. methyl iodide, dissolved in 20 ml. ethanol, are added. The mixture is additionally agitated for another hour, cooled at 20 C., and then the reaction product and the precipitated inorganic salts are vacuum-filtered. The residue is leached with ml. boiling ethanol and vacuum-filtered; the ethanol solution is then concentrated to half its previous amount.

7 The compound 3-acety1thio-methylthio-5-methylthio-4-cyanoisothiazole which precipitates is vacuum filtered.

Yield: 12.3 g.; M.P. 121-123 C. By analogy, 3-benzoylthio-methylthio-5-methylthi0-4- cyano-isothiazole is prepared; M.P. 114-115 C.

Example 2 Under stirring, 12.4 g. chloromethyl acetyl sulfide, dissolved in 10 ml. ethanol, are added dropwise to 21.8 g. of the disodium salt of 3,5-dimercapto-4-cyano-isothiazole, suspended in 300 ml. absolute ethanol. After two hours of agitation at 60 C., 12.6 g. dimethyl sulfate, dissolved in 20 ml. ethanol, are added dropwise. The reaction mixture is stirred for another two hours at 60 C., then cooled to 20 C., and vacuum-filtered. The residue is extracted with 150 ml. boiling ethanol and again vacuum-filtered. The ethanol solution is treated with activated charcoal and concentrated.

Yield: 5.5 g. of 3-acetylthio-methylthio-5-methylthio 4- cyano isothiazole; M.P. 120-122 C.

Example 3 11.3 g. of the potassium salt of 3-mercapto-5-methylthio-4-cyano-isothiazole are dissolved in 200 ml. ethanol and mixed, under stirring, with 6.2 g chloromethyl acetyl sulfide. Thereafter, the reaction mixture is heated for one hour to 60-70 C., then cooled to 20 C., and the reaction product is precipitated by the careful dropwise addition of Water. The 3-acetylthio-methylthio-5-methylthio-4-cyano-isothiazole is vacuum-filtered and recrystallized from ethanol.

Yield; 5.0 g.; M.P. 119121 C.

Example 4 21.8 g. of the disodium salt of 3,5-dimercapto-4-cyanoisothiazole are dissolved in 300 ml. water and mixed, at 510 C. under stirring, within minutes, with 14.2 g. methyl iodide. The reaction mixture is then stirred for another 1% hours at 510 C. and vacuum-filtered from the precipitated 3,S-dimethylthio-4-cyano-isothiazole, the latter being obtained as a by-product. The filtrate is concentrated to dryness, the residue is suspended in 150 ml. ethanol, and within 10 minutes, at 60 C., 11.2 g. chloromethyl acetyl sulfide are added dropwise to the suspension. After the addition is terminated, the reaction mixture is stirred for another hour at 60 C. Then, the inorganic residue is vacuum-filtered, and the mother liquor is concentrated to one-third its volume. The precipitated 5-acetylthio methylthio 3 methylthio 4 cyano isothiazole is vacuum-filtered and recrystallized from ethanol, with the addition of charcoal.

Yield: 5.3 g.; M.P. 70-71 C.

Here it is to be noted that the isomer produced by Examples 1-3 has the same melting point of 121 C.-* -2, whereas the isomer of Example 4 has a melting point of 70-71 C. This proves definitely that the two isomers can be produced, depending on the process employed. However, there is an outside chance that once the structures are firmly elucidated that the isomer stated to be produced by Example 4 will actually be that produced by Examples 1-3, and vice versa.

(B) PREPARATION OF THE FUNGICIDAL COMPOSITIONS isomer thereof) 75 Sulfite Waste liquor powder Na-isobutyl-naphthalene sulfonate 1 White bole 9 The above components are groundtogether. The thusproduced powder is sprayed or atomized in the form of a dilute aqueous suspension.

Example 6 Sprayable powder: Percent Copper oxychloride 7O 3 benzoylthio methylthio 5 methylthio 4- cyano-isothiazole (or the corresponding 5-, 3-

isomer thereof) 10. Oleic acid-N-methyl-tauride 5 Chalk 15 The above substances are finely. ground together. The thus-obtained powder can be diluted with water to form a suspension in the desired concentration. The suspension can be sprayed or atomized.

Example] Dusting composition: Percent 3 acetylthio methylthio 5 -methylthio' 4- cyano-isothiazole (or the corresponding 5-, 3-

isomer thereof) 15 Powdered sulfur 25 Kaolin 15 Pyrophyllite 42 Colophonium 3 Example 8 Sprayable powder: Percent S-acetylthio methylthio 3 ethylthio-4-cyanoisothiazole (or the corresponding 3-, 5-isomer thereof) 10 N-trichloromethylthio-phthalimide 40 Sulfite waste liquor powder 15 Na-isobutyl-naphthalene sulfonate 2 Chalk 33 R d-s1 I CN LSR1SC 0-3: 8

wherein R represents alkylene of 1-4 carbon atoms;

R represents alkyl of 1-4 carbon atoms, or X -phenyl wherein n is an integer of 13 and X is hydrogen, hydroxyl, alkyl of 1-4 carbon atoms, or halogen, or 2X represents methylenedioxy; and

R represents alkyl of 1-4 carbon atoms.

2. A compound as defined by claim 1 wherein the compound is represented by Formula Ia.

3. A compound as defined by claim 1 wherein the compound is represented by Formula 1b,

4. A compound as defined by claim 1 wherein the compound is 3-acetylthiomethylthio. 5 methylthio-4- cyano-isothiazole.

5. A compound as definedby claim 1 wherein the compound is S-acetylthiomethylthio 3 methylthio-4- cyano-isothiazole.

6. A compound as defined by claim. 1 wherein the compound is 3-benzoylthiomethylthio 5 methylthio-4- cyano-isothiazole.

7. A compound as defined by claim 1 wherein the and 9 10 compound is S-benzoylthiomethylthio 3 methy1thio-4- ALEX MAZEL, Primary Examiner cyano-isothiazole- R. J. GALLAGHER, Assistant Examiner References Cited US Cl X,-R.

UNITED STATES PATENTS 5 260-299, 455; 424-128, 141, 146, 181, 200, 227, 245, 3,155,678 11/1964 Hatchard 260-302 246, 249, 250, 263, 270

3,341,518 9/1967 Naito et a1. 260-302 

